Clinical and Experimental Endocrinology (CEE), Katholieke Universiteit Leuven, Leuven, Belgium.
Laboratory of Molecular Bacteriology, Rega-Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.
Front Immunol. 2022 Jun 9;13:902678. doi: 10.3389/fimmu.2022.902678. eCollection 2022.
The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D, can modulate both innate and adaptive immunity, through binding to the nuclear vitamin D receptor expressed in most immune cells. A high dose of regular vitamin D protected non-obese diabetic (NOD) mice against type 1 diabetes (T1D), when initiated at birth and given lifelong. However, considerable controversy exists on the level of circulating vitamin D (25-hydroxyvitamin D, 25(OH)D) needed to modulate the immune system in autoimmune-prone subjects and protect against T1D onset. Here, we evaluated the impact of two doses of dietary vitamin D supplementation (400 and 800 IU/day), given to female NOD mice from 3 until 25 weeks of age, on disease development, peripheral and gut immune system, gut epithelial barrier function, and gut bacterial taxonomy. Whereas serum 25(OH)D concentrations were 2.6- (400 IU/day) and 3.9-fold (800 IU/day) higher with dietary vitamin D supplementation compared to normal chow (NC), only the 800 IU/day vitamin D-supplemented diet delayed and reduced T1D incidence compared to NC. Flow cytometry analyses revealed an increased frequency of FoxP3 Treg cells in the spleen of mice receiving the 800 IU/day vitamin D-supplemented diet. This vitamin D-induced increase in FoxP3 Treg cells, also expressing the ecto-5'-nucleotidase CD73, only persisted in the spleen of mice at 25 weeks of age. At this time point, the frequency of IL-10-secreting CD4 T cells was also increased in all studied immune organs. High-dose vitamin D supplementation was unable to correct gut leakiness nor did it significantly modify the increased gut microbial diversity and richness over time observed in NOD mice receiving NC. Intriguingly, the rise in alpha-diversity during maturation occurred especially in mice not progressing to hyperglycaemia. Principal coordinates analysis identified that both diet and disease status significantly influenced the inter-individual microbiota variation at the genus level. The abundance of the genera and gradually increased or decreased, respectively in faecal samples of mice on the 800 IU/day vitamin D-supplemented diet compared to mice on the 400 IU/day vitamin D-supplemented diet or NC, irrespective of disease outcome. In summary, dietary vitamin D reduced T1D incidence in female NOD mice at a dose of 800, but not of 400, IU/day, and was accompanied by an expansion of Treg cells in various lymphoid organs and an altered intestinal microbiota signature.
维生素 D 的活性形式 1,25-二羟维生素 D 可以通过与大多数免疫细胞中表达的核维生素 D 受体结合，调节先天和适应性免疫。在非肥胖型糖尿病（NOD）小鼠出生时给予高剂量的常规维生素 D，并终生给予，可预防 1 型糖尿病（T1D）。然而，对于需要调节自身免疫倾向个体的免疫系统并预防 T1D 发病的循环维生素 D（25-羟维生素 D，25(OH)D）水平，存在相当大的争议。在这里，我们评估了从 3 至 25 周龄起，给雌性 NOD 小鼠补充两种剂量的饮食维生素 D（400 和 800 IU/天）对疾病发展、外周和肠道免疫系统、肠道上皮屏障功能和肠道细菌分类的影响。与正常饮食（NC）相比，饮食补充维生素 D 使血清 25(OH)D 浓度分别增加了 2.6 倍（400 IU/天）和 3.9 倍（800 IU/天），但只有 800 IU/天的维生素 D 饮食可延迟和减少 T1D 的发病率与 NC 相比。流式细胞术分析显示，接受 800 IU/天维生素 D 饮食补充的小鼠脾脏中 FoxP3 Treg 细胞的频率增加。这种维生素 D 诱导的 FoxP3 Treg 细胞增加，也表达外核苷酸酶 CD73，仅在 25 周龄的小鼠脾脏中持续存在。在此时点，所有研究的免疫器官中 IL-10 分泌的 CD4 T 细胞的频率也增加了。高剂量维生素 D 补充不能纠正肠道渗漏，也不能显著改变接受 NC 的 NOD 小鼠随时间增加的肠道微生物多样性和丰富度。有趣的是，在成熟过程中，α-多样性的增加尤其发生在没有进展为高血糖的小鼠中。主坐标分析确定，饮食和疾病状态都显著影响属水平上个体间微生物群的变化。与接受 400 IU/天维生素 D 饮食补充或 NC 的小鼠相比，无论疾病结果如何，在接受 800 IU/天维生素 D 饮食补充的小鼠的粪便样本中，属 和 的丰度分别逐渐增加或减少。总之，饮食补充维生素 D 可降低雌性 NOD 小鼠的 T1D 发病率，剂量为 800IU/天，而非 400IU/天，并且伴随着各种淋巴器官中 Treg 细胞的扩张和肠道微生物群特征的改变。
